The present invention relates to novel compounds that have activity at peripheral cannabinoid receptors, commonly designated the CB2 receptor class. Particularly these compounds are more specific for said CB2 receptor class than many other compounds active on cannabinoid receptors CB1 and CB2.
At least five different classes of cannabinoids have been identified: traditional tricyclic tetrahydrocannabinoids, such as Δ9-tetrahydrocannabinoid (Δ9-THC), synthetic bicyclic cannabinoids such as CP55,940 (see Little et al (1988)), aminoalkylindole such as WIN55,212 (see D'Ambra et al (1992)), endocannabinoid such as anandamide (see Devane et al (1992)), and pyrazole antagonists such as SR141716A (see Rinaldi-Carmona (1994)). Although the chemical structure of these cannabinoids differ markedly, all of them contain at least one oxygen that is hypothesized to be involved in binding of these drugs to brain cannabinoid (CB1) receptors.
Δ9-THC, the primary psychoactive constituent of the marijuana plant, and other tetrahydrocannabinols contain two oxygens; a phenolic hydroxyl at position 1 and an oxygen pyran ring on the opposite side of the molecule. The hydroxyl oxygen interacts with the CB1 receptor through hydrogen bonding with a lysine residue (Lys 192) (see Song and Bonner (1996)). The role of the oxygen of the benzopyran substituent of Δ9-THC is less clear; however it is known that opening of the pyran ring as in CP55,940 does not eliminate binding or in vivo activity (See Little et al (1988)). In the absence of a phenolic hydroxyl, as in 1 deoxyanalogs of Δ8-THC, orientation of the cannabinoid molecule with respect to the CB1 receptor may be inverted and the pyran oxygen may substitute as a substrate for hydrogen bonding with Lys 192 (see Huffman et al (1996), (1999)).
In contrast to the high binding affinity of CP55,940 and other similar pyran-ring open analogs the natural product cannabidiol is also a pyran-ring open compound yet does not bind to CB1 or CB2 receptors nor does it have a cannabinoid profile of effects in vivo Even the 1′,1′-dimethylheptyl analog of cannabidiol binds very poorly to the CB1 receptor. With this in mind the present inventors have studied the structural activity relationship of resorcinol derivatives which could be considered as cannabidiol analogs.
During this study, Hanu et al (1999) published synthesis and activity of HU-3-8, a dimethoxyresorcinol derivative that is a CB2 selective agonist. The transmembrane regions of CB2 receptors, which are involved in ligand recognition, exhibit 68% homology with those of CB1 receptors (see Munro et al (1993)). Showalter et al (1996) reported a high positive correlation (r=0.82) between binding affinities at these two cannabinoid receptors for cannabinoids in various classes; thus some of the structural features that enhance affinity for CB1 also enhance affinity for CB2.
Addition of a 1′,1′-dimethyl group to the lipophilic C3 side chain of Δ8-THC results in higher affinity for both receptors as compared to a nonbranched chain of identical length. Synthesis of a series of Δ8-THC analogs in which the phenolic hydroxyl at position 1 was removed (deoxy-Δ8-THC analogs) or was replaced with a methoxyl resulted in analogs with selectivity for CB2 receptors (see Gareau et al (1996); Huffman et al (1996)(1999)). Incorporation of an oxygen into a fourth ring attached at C1 also increased CB2 selectivity, suggesting differences in the interaction of oxygen in the binding pockets of CB1 and CB2 (see Reggio et al (1997)).
The present inventors have now provided bicyclic resorcinols in which the core chemical structure contains two hydroxyl or alkoxyl substituents positioned with a single intervening carbon in a benzene ring with a second cyclic substituent attached at the intermediate carbon.
In a first aspect of the present invention are provided novel compounds of general formula I

wherein:
R is selected from the group consisting of optionally substituted carbocyclic and heterocyclic rings;
R1 is independently selected at each occurrence from the group consisting of hydrogen and C1-6 alkyl;
R4 is selected from the group consisting of optionally substituted C1-10 alkyl or alkenyl;
and pharmaceutically acceptable salts, esters and tautomers thereof.
Preferred compounds of the invention have R as optionally substituted aryl, e.g. phenyl, cyclohexyl, cycloheptyl, cyclohexenyl, cyclopentyl, tetrahydrothiopyranyl, methandienyl, cycloheptyl, adamantanyl, tetrahydrothiophen-3-yl, 1-alkyl-piperidinyl, 4-aryl-cyclohexyl, 3,3-dialkylcyclohexyl, tetrahydropyranyl, 1-cyclohexanolyl, 1-4-dioxospirocycloalkyl, and cyclohex-3-enonyl.
Preferred compounds of the invention have R1 as hydrogen or methyl.
Preferred compounds of the invention have R4 as linear, C3-8 alkyl, eg. C5-7 alkyl, e.g., butyl, pentyl or hexyl.
Still more preferred compounds of the present invention have a group R6 at the 1-position of the ring R4 which is selected from the group consisting of hydroxyl and C1-3 alkoxyl, but more preferably more preferably hydroxyl. More preferred groups R4 are optionally substituted cyclic alcohols such as cyclopentan-1-ol, cyclohexan-1-ol, cyclohexan-1-ol and equivalent 1-ols of the other rings cited above as suitable for use as R4.
Substituents on the alkyl or alkenyl group R4 may generally be selected from electron withdrawing or electron donating groups such as is known in the art of cannabinoid chemistry, Conveniently, other than the hydroxyl or alkoxyl group at the 1-position of the ring R4, these will be selected from C1-6 alkyl and halo, but may be groups such as phenyl and heterocyclic rings.
A preferred group of novel compounds of the first aspect of the invention are of general formula II

wherein R1 and R4 are as described for formula I and R5 is C1-6 alkyl, more preferably methyl or ethyl. More preferably R1 is hydrogen or methyl, more preferably hydrogen. All isomers of compounds of formula II are of interest, but particularly preferred are isomer A and isomer B and the 3R-alkylcyclohexyl compounds, particularly compounds of formula
    2-(3-methylcyclohexyl)-5-(1,1′-dimethylheptyl)-resorcinol isomer A (0-1797)    2-(3-methylcyclohexyl)-5-(1,1′-dimethylheptyl)-resorcinol isomer B (0-1798)    2-(3R-methylcyclohexyl)-5-(1,1′-dimethylheptyly)-resorcinol (0-1826).
Still more preferred are the hydroxyl derivatives of these compounds which are the 1-{4-(1,1-Dimethyl-heptyl)-2,6-dimethoxy-phenyl}-3-methyl-cyclohexanol compounds O-2137 and its racemates O-1966 and O-1967.
A second aspect of the present invention provides a method of treating a patient in need of therapy for pain, particularly peripheral pain and/or inflammation or autoimmune associated disease comprising administering to that patient a therapeutically effective amount of a compound of formula I, more preferably of formula II. Such amount will typically be administered in a pharmaceutically acceptable carrier, such as is well known in the art.
A third aspect of the present invention provides a composition comprising a compound of formula I or II together with a pharmaceutically acceptable carrier and/or excipient. The composition should be sterile and, if intended for injection, non-pyrogenic.
Administration of the aforementioned compounds of the invention or a formulation thereof need not be restricted by route. Options include enteral (for example oral and rectal) or parenteral (for example delivery into the nose or lung or injection into the veins, arteries, brain, spine, bladder, peritoneum, muscles or subcutaneous region). The treatment may consist of a single dose or a plurality of doses over a period of time. The dosage will preferably be determined by the physician but may be between 0.01 mg and 1.0 g/kg/day, for example between 0.1 and 500 mg/kg/day. In terms of dose per square meter of body surface, the compound can be administered at 1.0 mg to 1.5 g per m2 per day, for example 3.0–200.0 mg/m2/day.
Whilst it is possible for a compound of the invention to be administered alone, it is preferable to present it as a pharmaceutical formulation, together with one or more acceptable carriers and/or excipients. The carrier(s) and/or excipients must be “acceptable” in the sense of being compatible with the compound of the invention and not deleterious to the recipients thereof.
The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. A unit dosage form may comprise 2.0 mg to 2.0 g, for example 5.0 mg to 300.0 mg of active ingredient. Such methods include the step of bringing into association the active ingredient, i.e., the compound of the invention, with the carrier and/or excipients which constitute one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers and/or excipients and/or two or all of these, and then, if necessary, shaping the product.
Formulations in accordance with the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropyl-methyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, PVP, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide desired release profile.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouth-washes comprising the active ingredient in a suitable liquid carrier.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which may render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose or an appropriate fraction thereof, of an active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
In a fourth aspect of the present invention there is provide a compound of the first aspect of the invention for use in therapy.
In a fifth aspect of the present invention there is provided the use of a compound of the first aspect of the invention for the manufacture of a medicament for the treatment of a pain, inflammation and autoimmune disease.